1. Field of the Invention
This invention pertains to controlled release tacrine drug delivery systems. The novel drug delivery systems contain an immediate release composition and a sustained release composition. Therapeutically effective amounts of the drug delivery systems may be utilized in a wide variety of pharmaceutically acceptable carriers to prepare medicated controlled release compositions. This invention also relates to methods for preparing and using these drug delivery systems and the medicated controlled release compositions in which they may be employed.
2. Description of the Background
Tacrine (1,2,3,4-tetrahydro-9-acridinamine hydrochloride) is a reversible cholinesterase inhibitor used as a respiratory stimulant in clinical anesthesiology for the reversal of postoperative sedation and prolongation of the muscle relaxation effect of succinylcholine. Tacrine has recently been shown to be a cognition activator and to improve some symptoms in Alzheimer's patients. Absorption and elimination half-life studies on tacrine have shown that the drug is rapidly absorbed and eliminated and that frequent administration is required to maintain therapeutic blood levels. Because treatment of Alzheimer's disease is long term, frequent administration of tacrine can be inconvenient and wide swings in blood levels may cause adverse effects. Hence, controlled-release forms of tacrine which release the drug uniformly over an extended period of time are more advantageous than conventional dosage forms.
Sustained release compositions for the sequential or timed release of medicaments are well known in the art. Generally such compositions contain medicament particles, normally administered in divided doses two or more times daily, mixed with or covered by a coating material which is resistant to degradation or disintegration in the stomach and/or in the intestine for a selected period of time. Release of the medicament may occur by leaching, erosion, rupture, diffusion or similar actions, depending upon the nature and thickness of the coating material.
A frequently encountered problem in the field of sustained release compositions is that many water-miscible drugs have a tendency to be dumped or surged into the body during the first hour or two after an oral dosage form is ingested. This problem is particularly acute when the sustained release compositions are administered with food.
U.S. Pat. No. 4,728,512, issued to Mehta et al., discloses a therapeutic composition containing three types of spheroids containing a medicament. The first type of spheroids are uncoated and provide an immediate release form, the second type of spheroids are coated with a pH sensititve material such as copolymers of methacrylic acid and methacrylic acid methyl ester or polyvinyl acetate phthalate, and the third type of spheroids are coated with a pH independent material having an undercoating selected from the group consisting of hydroxypropyl methylcellulose and hydroxypropyl methylcellulose containing carboxymethylcellulose or sodium starch glycolate and an overcoating of a neutral polymer based on polymethacrylic acid esters.
While the above sustained release compositions provide some degree of improved sustained release activity, none of the above compositions are entirely satisfactory. The present invention provides improved controlled release tacrine drug delivery systems without the disadvantages characteristic of previously known products. The present invention also provides methods for preparing and using these improved controlled release drug delivery systems and the medicated sustained release compositions in which they may be employed.